Process for the preparation of 1-dibenzylamino-2-haloethanes and salts thereof



Patented Feb. 6, 1951 PROCESS FOR THE PREPARATION OF I-DIBENZYLAMINO- 2-HALOETHANES AND SALTS THEREOF Thomas F. Wood, Clifton, N. J assignor toBurton T. Bush, Inc., New York, N. Y., a corporation of New Jersey NoDrawing. Application June 5, 1948, Serial No. 31,40?

6 Claims. (Cl. 260--570.9)

This invention relates to a novel process for preparing l-dibenzylamino2 haloethanes and salts thereof.

The products made in accordance with my process have recently foundmedical significance of unusual degree. Recent and current medicalliterature include a number of reports on scientific investigationswhich clearly tend to establish the unique sympatholytic and adrenolyticcharacteristics of these substances. Unfortunately, however, as in thecase of many newlyfound medicinal agents, the cost of the aforementionedproducts is quite high. It would represent a considerable advance,consequently, if the cost could be reduced. My present invention isbelieved to represent such an advance.

I have found that excellent yields of the amino haloethanes can beobtained in accordance with my technically-feasible novel process whichcomprises treating 1-amino-2-haloethane hydrohalides or l-benzylamino 2-haloethane hydrohalides with benzyl halides in the presence of aneutralization or so-called acid-binding agent at elevated temperatures.The resulting amino haloethanes can be readily isolated and purified byfiltration and vacuum distillation.

If desired, the salts of the amino haloethanes may be prepared from thecrude or purified amino haloethanes by treating the latter with suitableamounts of acids such as hydrochloric, hydrobromic, sulfuric, nitric orphosphoric acids.

As far as I am aware, no suitable method has previously been availablefor the aralkylation of l-amino 2 haloethanes and 1-benzylamino-2-haloethanes. These substances are difficult to isolate in the pure stateowing to-their instability and strong tendency to undergo reactionsinvolving increase in their molecular size. Such amines have beenisolated in the form of their salts, such a their hydrochlorides orhydrobromides, and when the free amines have been desired they have beenliberated from their salts by treatment With alkali in a suitablesolvent. Even after the aforementioned costly purification process isfollowed in order to obtain the amino haloethanes in reasonably purecondition, it has been found that known aralkylation processes,involving the treatment with benzyl halides to form the correspondingsalts of the benzylsubstituted amino haloethanes followed by liberationof the free amines by. treatment with alkali, do not yield the desiredproducts. Instead, large quantities of high melting material, probablydimers or polymers of the desired amines, are obtained.

In view of the. foregoing. it was: surprising to find that the desireddibenzyl-substituted 1- amino-2-haloethanes could be prepared inexcellent yields by treating the salts of either thelamino-2-haloethanes or 1-benzylamino-2-haloethanes with benzyl halidesin the presence of acid-binding agents. Upon completion of thebenzylation, the desired free amines can be obtained in substantiallypure form by suitable distillation preceded by a filtration.

Among the salts which I may use as starting materials in my'process are1-amino-2-ch1oroethane hydrochloride, l-amino-Z-bromoethanehydrochloride, l-amino-Z-chloroethane hydrobromide,l-amino-Z-bromoethane hydrobromide, 1-benzylamino-2-chloroethanehydrochloride, 1- benzylamino-Z-bromoethane hydrochloride, 1benzylamino-2-chloroethane hydrobromide and l-benzylamino-Z-bromoethanehydromide.

As benzylating agents benzyl chloride or benzyl bromide may be used.

My novel process may be conducted in th presence of suitable solvents,if desired. Examples of such solvents are benzene and toluene, but othersolvents which are inert under the reaction conditions and which arecapable of forming azeotropes with water can be used. I have found thatexcellent results are obtained if no solvent at all is employed otherthan an excess of the benzyl halide itself.

As the acid-binding agent I have found that sodium carbonate and sodiumbicarbonate give excellent results. Other alkali metal carbonates andbicarbonates give satisfactory results, as well as alkaline earth metalcarbonates and bicarbonates. The recitation of the foregoingacid-binding agents is not to be taken as limitin my invention thereto,for even such a strong acid-binding agent as sodium hydroxide can beused to effect my process; the use of such a strong agent not beingrecommended for best results, however.

With regard to the amounts and concentrations of the reactants, thesemay be varied over wide limits as will be understood by organicchemists, It is advantageous to use at least from 2 to 4 moles of benzylhalide per mole of l-amino- 2-haloethane hydrohalide or l-benzylamino-2-haloethane hydrohalide. Enough acid-binding agent to fix or neutralize 2moles of hydrohalide for each mole of amino haloethane hydrohalide usedshould be employed. When alkali metal carbonates and bicarbonates suchas sodium carbonate or sodium bicarbonate are employed it has been foundthat an excess of from about 10 to about 30 percent of these reagents,over the theoretical amounts, gives advantageous results.

The temperatureand time of reaction may also 3 4 vary and depend in parton factors such as the of crude hydrochloride equaled 87 percent ofsolvent, if any, used and the reactants employed. theory. The crudehydrochloride was dissolved Temperatures within the range of from about30 in 600 grams of n-butanol at 85 C. and, after C. to about 150 C. givesatisfactory results but stirring with 5 percent of decolorizing carbonfor I prefer to employ temperatures between about 5 minutes, wasfiltered. On cooling and filtering 50 C. and 120 C. off the crystals anddrying, there was obtained The reaction period varies from a few hoursto 202 grams of snow-white 1-dibenzylamin0-2- a few days. When sodiumbicarbonate is emchloroethane hydrochloride, M. P. 192-194 C. ployed thereaction is sufliciently complete in 6 to 8 hours at 7080 C.; while inthe case of i0 EXAMPLE 2 sodium carbonate from 24 to 36 hours arerequired preparation. of 1dwemyzammmz chlomethane for completion of thereaction under the same conditions.

hydrochloride Atmospheric and sub-atmospheric pressures a l-litel,3-ne0k fl provided with an can be employed m my 171106655 Pressures@510, 1 agitator, thermometer and reflux condenser Was it WOW Z0 (0 llmm. 0/ marry 1W6 given 111W" ll Ill M Mr W W/ t g my ((4rd; (4 4/ an beemp o (1.58 mole) an as about to 30 mm. of mercury have giv 200 grams(if maria; cgfgizte (Soda ash) (0.75

ms 0 so Satisfactory results. hydrohalides employed 30 gra,

The amino haloethane (16 mole).

rocess are easily ma tirrmg: as startmg li asa fgkfie materials. For ei-20 There was added w s moroethane hydrofrom r nifio-fl-chloroethanehydrochlorine 29 grams of Lamm'o-Z-c ample, ha ly quantitative Yleld co1 chloride (0.25 mole)- tred can be made In I 1 hydrous bammmz-etnm'mwas warmed to 50 C. and S 1 d verting commercieia f llowed by treatmentwith The mlxmre 50 58 C. The Salt was filtele. into its hydrochloride,zylamino-2-chlorofor 25 hours at 'tlglzo cc. of Warm benzol' Thls tmonylchlondie' (Q ilt l1} 196l98 0.) can be off and washed W1 ethane hydrocori 0/ M16771] m; j J v on coolin and d with the filtrat 1 tiOn 5 1 gbenzalde was C(PmbIHB d from the so u prepared in mgr! meld tggglniomwedby cam Standmg ll e fge j erial which was fi ifled hyde with i-amino-f161d 1 benZy1aminO-2- grams of crysta mzwxazolidone. ter lstlllln lyhvdrogenemn ted with thionyl c off and found to be moving excess ben ylchlorlde ethanol, which is then t1 eanve into its droff the benzol andSure there was btained fl?) ride at '70-3 fast co e thi nyl chlorideunder reducedp d, Th s was thechloride and then treated W1 grams ofreddish m of alco ol and the hyat describe m inventim the Solved 1 3335.by passing in HCl ga In Order more fully :Ven is understood drochlondeWa? d18 grams of l-dibenzylam fofollowing examples are g1 ,uu and othere w s obtaine hlo M. R 192L194 p, that they are for Purposes of 1z-chioroethane lfif gfimes niy invention, which ing 1 e hmltatmn.EXAMPLE 1 3x 2 to be l mited theregyebgt a rmissi1-diben2yZamino-2-chloroethane 0 construed as g g z 23 by the apparation of hydrochloride the prior art an claims. I Of: '1 claim: 7 1y1a,yn1nO- A bhlck 01mm 1 mino-2-chloroethane hyr 1, The process forlf zziggg actin a sub- 198 grams of f miia z-haloethanes, Whlc c youconsisting of r pr V Z j l a fi/wf I My 1r J-fle/w/flfl ma /Zpl c 15 i!".9 I 0010 1126.? Q I0 L911? 0; I pIISl] -UU0-5-Gp]0Lag pggg p21 I 62?Lsscrma 9 311/ V WW warm u I 0/9/1112 1 b t WWW m 1 min/6 [Willi/N mmm...

6. The process for preparing 1-dibenzylamino- 2-ch1oroethane, whichcomprises reacting about 1 mole of 1-benzylamino-2-chloroethanehydrochloride and about 2 to 4 moles of benzyl chloride in the presenceof at least about 2 moles of sodium bicarbonate at a temperature withinthe range of about 50 C. to about 120 C.

THOMAS F. WOOD.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date 1,949,247 Eisleb Feb. 27, 1934OTHER REFERENCES Peacock: J. Chem. Soc. (London), vol. 125, pages1975-1980 (1924).

1. THE PROCESS FOR PREPARING 1-DIBENAYLAMINO2-HALOETHANES, WHICHCOMPRISES REACTING A SUBSTANCE SELECTED FROM THE GROUP CONSISTING OF1-AMINO-2-HALOETHANE HYDROHALIDE AND 1-BENZYLAMINO-2-HALOETHANEHYDROHALIDE AND A BENZYL HALIDE IN THE PRESENCE OF AN ACID-BINGING AGENTAT ELEVATED TEMPERATURES.